Heterosexual transmission is now the predominant source of new HIV infections and the number of infections in women is on the rise. In developed countries, the effectiveness of HAART therapy has allowed HIV-positive men and women to live longer. It has been predicted that by 2015, approximately 50% of people in the USA living with HIV will be above 50 years old (http://www.sfaf.org/hiv-info/hot-topics/hivision/hiv-and-aging-vienna- satellite-2010-07-19-executive-summary.pdf). This will result in a massive increase in health care costs in order to provide for antiretroviral drugs as well as to manage the multitude of adverse effects that occur with long-term usage of these drugs (http://www.gmhc.org/files/editor/file/a_pa_aging10_emb2.pdf). Although it is known that aging results in loss of sex hormones and reduction of certain immune functions (reviewed in Wira et al, Am J Reprod Immunol. 2011 Mar;65(3):196-211),there remains a major gap in our understanding regarding the extent of loss of innate immune functions in the female reproductive tract (FRT). As multiple innate immune factors of the FRT are hormone-responsive, the loss of estrogen (and/or progesterone) with aging can result in a loss of protective mechanisms that make women more susceptible to sexually transmitted infections, such as HIV. In case of HIV-positive women, this can result in an increased probability of sexually transmitting HIV to a non-infected partner. Our proposal will examine the hypothesis that significant changes occur in the reproductive tract of postmenopausal women resulting in an increased susceptibility to acquiring sexually transmitted HIV. Specifically we will determine the levels of protective endogenous anti-HIV factors (SLPI, Elafin, MIP3a/CCL20 and human beta defensin 2 (HBD2)) in genital tract secretions of pre- and postmenopausal women and correlate these values with anti-HIV activity in the same secretions. We will also examine the biological activity of the endogenous anti-HIV factors by correlating with the levels of proteases known as Cathepsins (specifically B, D, and G) that are known to activate/deactivate the aforementioned anti-HIV factors. The proposed adds a new dimension to a grossly under-studied area of HIV research and will provide us with a unique outlook on susceptibility of postmenopausal women to sexually transmitted HIV. The outcomes will be significant because the data from this study can be used to develop therapeutic interventions specifically designed to boost genital tract immunity in older women. PUBLIC HEALTH RELEVANCE: Women are disproportionately affected by the HIV/AIDS epidemic, and aging women may develop increased susceptibility to HIV due to loss of immune functions as a result of sex hormone decline at menopause. Our proposal will examine innate immune functions in the genital tract of postmenopausal women to determine whether a less robust immune system might make these women more susceptible to acquiring as well as transmitting HIV.